Micromet– More Reasons For Optimism


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Two weeks ago, Micromet (MITI) hosted its annual R&D day, where it discussed plans for 2009 and beyond. The meeting provided plenty of information regarding the company’s technology and drug candidates, but more importantly, it served as an appetizer for next month’s EHA meeting. As a reminder, Micromet is expected to present data from 2 trials evaluating its lead agent, blinatumomab (MT103), in two forms of blood cancer: Non-Hodgkin Lymphoma (NHL) and Acute Lymphoblastic Leukemia (ALL).

During the R&D day, the company (intentionally and unintentionally) shared some previously undisclosed results from the trials. The new information, which includes impressive efficacy signals from both studies, further solidifies blinatumomab’s position as one of the most promising investigational agents in oncology. Based on its spectacular performance, blinatumomab has a high chance of getting approved as soon as 2012.


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Fast route to market

Although the NHL study represents a much larger commercial opportunity, the ALL trial will garner most of the attention. As I explained in my previous article, the ALL study evaluates blinatumomab’s effect on patients who have undergone chemotherapy but still have disease remnants in their bone marrow (minimal residual disease or MRD).  These patients usually have very poor prognosis since they are destined to relapse within less than a year. The only available treatment option for some of these patients is stem cell transplant, a highly aggressive and toxic procedure which is associated with a 20-30% mortality rate. Micromet decided to enroll only patients who cannot tolerate or are unwilling to undergo stem cell transplant, as these patients have no approved treatment options.  

The high medical need combined with the low prevalence of ALL make this clinical program a fast route to market, with a possible approval already in 2012. More importantly, the study could serve as the ultimate proof of concept for blinatumomab’s ability to deal with one of the central challenges in cancer, post-treatment residual disease that eventually leads to disease relapse.

Micromet’s strategy is similar to that of other biotech companies, such as Exelixis (EXEL) and Arqule (ARQL). All three have a promising compound with a very large potential market, but they decided to pursue approval for niche indications that represent the fastest and safest route to approval. Micromet’s blinatumomab targets CD19, a protein highly expressed on the majority of blood cancers, but decided to initially go after a distinct subgroup of ALL. Exelixis’ XL184 hits several targets that are relevant in most solid tumors, yet it decided to seek approval for a rare subset of thyroid cancer. Arqule’s lead compound targets c-Met, a protein believed to have a role in a plethora of solid tumors, but it decided to start with a family of rare tumors called MiT. Based on clinical data the companies have presented, their chances of obtaining an FDA approval are high.


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Reasons for optimism

Data from the ALL trial could shed light on two basic questions:

1)      Can blinatumomab effectively convert MRD positive patients into an MRD negative status?  

2)      Can the MRD conversion be translated into real clinical benefit in the form of longer remission and survival?

For the first question, the answer is a resounding “yes”. Last year, Micromet presented preliminary data on just four patients, three of which turned from MRD positive to MRD negative. A conversion rate of 75% using such a stringent parameter is impressive, but it is very hard to conclude anything from such a small sample size. Next month at EHA, the company will present results for ~17 patients, still a small number but a much more reliable one. The exact conversion rate for these patients will be announced next month, but it will probably be very high, according to a statement by one of the speakers who revealed that “almost all” of the patients responded to blinatumomab.     

But response is not the ultimate parameter for these patients, who typically experience a relapse within 6 months following initial therapy. Therefore, the real issue is whether blinatumomab can keep patients in remission for a longer period of time.  The majority of patients were recruited to the study only in the past six months, following the previous data at ASH, so the duration of responses will probably be available for a limited amount of patients. The company provided anecdotal evidence for blinatumomab’s effect in two patients, who were still in remission for 9 and 10 months, respectively. It is important to understand that in most cases, there is an average lag of several months between a molecular relapse (turning from MRD negative to MRD positive) and a clinical relapse, where a large amount of cancer cells is found in the bone marrow. Therefore, the two patients are looking at a time to relapse of over a year at minimum. This is highly encouraging, considering the fact that most patients in this setting experience disease relapse within 6 months.

On top of the anecdotal data, there is a good reason to believe that MRD conversion will be translated into longer remission and overall survival, perhaps even a cure. Many studies have shown that patients who are MRD positive following initial treatment have a very high risk of relapse as opposed to MRD negative patients who have a high likelihood of long term remission. MRD is not just another surrogate that can predict patient prognosis, it is the presence of the disease itself. As a bone marrow disease, ALL originates in the bone marrow and spreads to the blood and other organs as the disease progresses. Therefore, if blinatumomab manages to purge the bone marrow to the point where even the most sensitive method cannot identify cancer cells, then curing these otherwise terminal patients is not out of the question.   


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MT110- Micromet’s wild card

The next big event for Micromet is the ESMO meeting in September, where the company will present phase I data for MT110, the first BiTE antibody for the treatment of solid tumors. At the R&D meeting, the company did not provide any data about the ongoing trial which commenced one year ago. Assuming a relatively slow accrual rate of 1 patient per month, the study has only recently reached doses that could show some sort of clinical activity. During the summer, the trial might reach dose levels at which multiple objective responses were observed in blinatumomab’s dose escalation phase I trial. Since MT110 targets solid tumors, as opposed to blinatumomab which targets blood borne malignancies, the company will probably have to push MT110’s dose higher compared to blinatumomab’s dose.  Therefore, it is impossible to predict whether MT110 will prove to be clinically active, but if it will, investors might have to wait to next year to see real clinical responses.

Until data becomes available, investors might be encouraged by the recent European approval of another bispecific antibody which is very similar, at least conceptually, to MT110. Last month, TRION pharma (another Munich based company) announced that its lead antibody, Removab has been approved by the EMEA (the European equivalent of the FDA) for the treatment of ovarian cancer. Similarly to MT110, Removab is a bispecific antibody that targets CD3 with one arm and EpCAM with the other. The recent approval of Removab is important because it serves not only as a validation of targeting EpCAM with a bispecific antibody, but also because it utilizes a similar mechanism of action to that of MT110.

TRION’s technology could be viewed as a threat to Micromet’s position as the leader of bispecific antibodies, but at the moment, TRION’s  platform suffers from multiple drawbacks. These drawbacks, especially the drug’s safety profile and immunogenicity, substantially limit the potential use of TRION’s products. In the meantime, there is no evidence TRION was able to work around these issues, which leaves Micromet as the undisputed leader.


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Portfolio update and performance

We decided to increase our position in Micromet ahead of the blinatumomab data next month. 2009 has the potential to be a transformative year for Micromet, with multiple value creation events, including at least one licensing deal and a data set that could serve as a basis for a registration trial next year. On a cautionary note, notwithstanding Micromet’s huge upside potential, it is still a high risk play due to the novelty of its technology and the early stage of its programs.

Since its inception 7 months ago, the biotech portfolio, co managed by Ran Nussbaum and myself, generated a return of 22.9%, versus 5.7% and 2.1% for the NASDAQ and S&P, respectively. In addition, the portfolio outperformed all the leading Life Sciences indices and ETFs, including the AMEX Biotechnology (^BTK) Index and the NASDAQ Biotechnology Index (^NBI), represented in the table below by the iShares NASDAQ Biotechnology (IBB) ETF.

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                                    Portfolio holdings as of May 8th 2009

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25 thoughts on “Micromet– More Reasons For Optimism

  1. ..THE best blog in the pharma side…very thorough analysis.Thank you.
    I do own Micromet.Can you give your opinions about Poniard and Chelsea Therapeutics.I do think both have chances of explosiv growth…Awaiting your views…

    Like

  2. Thanks

    Poniard has a nice drug and a reasonable chance of success in SCLC. I guess people are worried about potential competition from Celgene’s amrubicin. With respect to other indications, we’ll know more after ASCO.
    I don’t follow Chelsea Therapeutics closely.

    Ohad

    Like

  3. Hi Ohad,

    Great blog site with very helpful information. I have a question regarding SNTS. You put it in portofolio last Oct with note of more comments later. I couldn’t find any additional comments on why SNTS is in the portofolio.

    Thanks.

    Like

  4. Hi Alex

    The deal is positive and could be leveraged to get some highly needed $$$. I have to say I was somewhat disappointed by the deal terms which were probably a result of the company’s weak balance sheet. ROSG decided not to dilute its shareholders for the time being, but it seems it will have to, sooner or later.
    The company’s technology is still one of the most exciting stuff in biotech imo.

    ohad

    Like

  5. Hi Ohad, Incyte is finally taking off today…it was mentioned on some news on Friday. Were you going to do a write up on them soon? TIA.

    Like

  6. INCY is looking really good recently.
    I hope it implies that the debt issue is going to be resolved soon. Unfortunately, I am limited in the amount of articles I can write, for every 3-4 pieces I want to publish I can do only one, so I can’t promise anything, but INCY is definitely one of the stocks I follow closely and would love to do a write up on it.
    The following posts will probably be about ASCO related news.

    ohad

    Like

  7. Hi. Ohad:
    You mentioned “TRION’s platform suffers from multiple drawbacks. These drawbacks, especially the drug’s safety profile and immunogenicity, substantially limit the potential use of TRION’s products.”

    Could you please provide more detailed info on what are specific drawbacks of safety and immunogenicity of Trion’s Removab?

    Another question is while MT203 is also targeted EpCAM as does MT110, MT203 is in phase 2 and MT110 is in phase 1, could you please compare those two and also explain why you would say MT110 is a wild card while MT203 is not?

    Thanks

    Like

  8. Hi Bill

    From I understand, in order to overcome stability and production issues, TRIOMABs are half mouse half rat. This is in contrast to most commercial antibodies, which are mainly made of human sequences. As a result, the immune system identifies TRIOMABs as foreign objects and neutralizes them, so they cannot be given for a large number of cycles.
    Regardless, TRIOMABs also lead to increased cytokine release that leads to adverse events. Actually, this is exactly what I was afraid of in MITI’s case but so far so good…

    This is why Removab was not developed as a systemic treatment (IV) but was injected into the peritoneal cavity.

    There might be something I am missing, but as far as I can tell, MITI’s platform is far superior.

    I assume you are referring to MT201 (MT203 is the anti- GMCSF antibody), which is a conventional antibody whereas MT110 is BiTE antibody. MT110 is a wild card because it has no clinical data but if it works, it’s going to be huge. MT202 on the other hand, has plenty of data and so far results are not exciting.

    Ohad

    Like

  9. Ohad:

    Thanks very much for your reply.
    I appreciate your analysis and insight.

    I share with your concern on MITI’s antibody source. I read some articles on MITI’s MAb which are from mouses. Hence it may induce immune rejection in humans. As you described that Removab MAb souce is half from mouse and half from rat. This is even worse, being more likely to induce immune rejection.

    However, sgen and imgn do not use pure human antibody either from what I read a few years ago. They are using “humanized” antibodies. It changed some chemical structure to make it look like human and not 100% pure human. Hence I guess it may be still possible to induce immune rejection to some minor degree.

    There has been two companies abgx (acquired a few years ago) and medx, which can produce full human antibody.

    I guess if MITI can use Mederax pure human antibody, that will be an ideal match.

    Like

  10. There is no concern with regards to MITI’s antibody source, as they use humanized antibodies as far as I know. TRION do not use chimeric or humanized antibodies but entirely non-human sequences, which is why patients develop an immune response against the drug.

    What I meant to say is that both TRION and MITI use similar mechanisms of action which could lead to production of cytokines. So far, MITI’s safety profile is clean as opposed to TRION’s safety profile which is problematic. It has nothing to do with immunogenicity.

    Besides ABGX and MEDX, there are also CAT (now part of Medimmune) and Morphosys, which I previously wrote about. MITI could license the technology but based on the evidence thus far, there is not much of an advantage for fully human antibodies in terms of immune response.

    Best,
    ohad

    Like

  11. Ohad: Hi.

    Are you very sure that MITI BiTE are humanized MAb?

    I saw you said in your blog that MITI BiTE is humanized or chimeric MAb.

    Did you get that info from any professional journal article?

    From what I read on many professional journal articles about MITI’s BiTE so far in which they all stated that MITI BiTE are made from mouse MAb.

    I would like to confirm this whichever way it may be.

    Thanks very much in advance.

    Like

  12. So when both TRIOMABs and MITIs Abs are nonhumanized does MITI still have an edge? In fact I intended to buy MITI but now I am not that sure. TRIomas Ab is immonogenic (probably published) and MITIs not or this information is not avialable?

    More general question – how different two antibodies (or biologics in general} have to be in order to be approved as two different therapeutical entities? And back to MITI is there a chance that it will be approved in Europe with TRIOMAB already approved?

    Thanks for your answer.

    Like

  13. MITI still has an edge because its antibodies consist of the variable regions only, as opposed to TRION whose abs are whole antibodies (variable+ constant regions). Most of the immunogenicity is caused by the constant regions so it that sense, MT103 is as immunogenic as Rituxan or Erbitux, which are chimeric antibodies.

    Theoretically, even a slight difference in the amino acid sequence of a protein can lead to different/better/worse function so this could be regarded as a different drug.
    However, the issue is very complicated because there are a lot of factors, especially intellectual property issues that may prevent the generation of similar proteins.

    With respect to MITI’s MT110 vs. TRION’s Removab, there is no such problem, as the two abs are totally unrelated. The only challenge MT110 will face is succeeding in a registration trial.

    ohad

    Like

  14. Thanks for your answer.
    One more thing came to my mind. How is it with offlabel use of anticancer drugs? TRION was approved for ovarian cancer but doctors might start using it for other malignacies including MRD. Selection of the diseases might be based on the results of ongoing MITIs clinical trials. Does this block MITIs future drug penetration? I mean wouldnt doctors stick to product they already have possitive experience even if they use it offlabel? This might be a naive question, I simply dont know how difficult it is (from the point of law and usual praxis) to use something offlabel in situation when there is or is not an alternative. I am looking forward to your opinion.

    Like

  15. Off label use happens in oncology, but only if physicians have a very good reason and providing the drug is safe. TRION’s drug is not approved for systemic therapy (intravenously)due to its prolbematic safety profile. This could change, but at the moment, I doubt that anyone would use it outside of the approved indication.
    If by MRD, you meant ALL, don’t forget that TRION’s antibody is not relevant for ALL. It may compete with MT110 in the future for solid tumors, if both agents get approved, but that’s a big “if”.

    To sum it all up, MITI is facing a lot of challenges, but TRION’s Removab is not one of them, at the moment.

    ohad

    Like

  16. Hi. Ohad:
    http://messages.finance.yahoo.com/Stocks_(A_to_Z)/Stocks_M/threadview?m=tm&bn=27685&tid=5273&mid=5273&tof=4&frt=2
    Regarding CNS adverse events:
    “Predominantly during the first days of treatment, symptoms of the CNS, such as disorientation, confusion, speech disorders, tremor and convulsions, have been observed in some patients (7 out of 39 lymphoma patients, Grades 2 and 3). The nature of CNS events is not yet fully understood. So far, all CNS-related events were fully reversible during or shortly after discontinuation of treatment. Most adverse events, including CNS-related events, occurred during the first 3 days of treatment. In contrast, during several weeks of maintenance treatment, a much reduced incidence and intensity of adverse events have been observed. Most AEs (>95%) returned to grade ≤1 during ongoing treatment.”

    Would you please give a guess here about that MT103 CNS adverse events are mostly related to T Cell cytokines’ effect or something else, since immunogenecity would not be a big issue here?

    Thanks

    Like

  17. From what I recall, the company believes that the CNS events are caused by lymphoma cells in the CNS. My impression is that investigators can now identify these patients in advance and use low sneak-in dose as mitigation measure. I didn’t hear anything about immunogenicity in that context.

    ohad

    Like

  18. Hi. Ohad

    I always appreciate your insight and analysis on biotech.

    Assuming CNS events are due to lymphoma cells, then CNS events will only happen in lymphoma patients who may have lymphoma cells in their brains. Hence CNS events will not happen in ALL(Acute Limphocytic Leukemia) patients who do not have lymphoma cells in their brains.

    May I know MT103 CNS events only occur in lymphoma patients and never occur in ALL patients at all?

    Thanks

    Like

  19. MITI said the issue of CNS events and identifying patients who are likely to develop them will be discussed in full detail at ASH, so everything is still pretty vague.
    Most CNS events are from the NHL study, which involves
    higher doses. I don’t know whether there are other reasons besides the dose that could explain the difference.

    ohad

    Like

  20. Ohad,
    a few questions.
    What molecular characteristic is used for monitoring of MRD? Is it the protein MT103 binds to?
    Is there any plan for situation that some of the pacients successfully trated with MT103 gets molecular relapse? Will MT103 tried again to keep the clone at bay? Would the cells still react?

    What is your opinion on todays rise +40% and following sell off? Was it because the investors dont understand MRD concept? Or they see target group as a very small?

    Thank you for answers.

    Like

  21. Hi beo,

    MRD is the presence of tumor cells in the bone marrow, it is measured by looking at specific mutations the patients harbor.
    MT103 binds CD19, which is present on tumor cells. It has nothing to do with the identification of MRD.

    I am not aware of cases of retreatment following relapse. It’s impossible to tell for sure whether patients will still respond to MT103.

    I can’t explain the stock’s behavior, but the data was very positive.

    ohad

    Like

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